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1.
Arch Sex Behav ; 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-31309429

RESUMO

Risky sexual behaviors are important factors driving the HIV/AIDS epidemic. Although Zambia experiences a high HIV prevalence, especially among youth, there is a dearth of information regarding risky sexual behaviors among young adults. Therefore, we investigated the prevalence and associated factors of risky sexual behaviors among college students in Lusaka, Zambia. A cross-sectional study was conducted in February 2017 among 427 college students at the University of Zambia. Participants reported their sexual behaviors, sexual attitudes, and lifestyle using self-administered questionnaires. Multinomial logistic regression models were employed to assess potential determinants of risky sexual behaviors. Among the 205 students who reported ever having sex, 148 (72.2%) engaged in risky sexual behaviors in the last 12 months. Participants who were older (OR 1.30, 95% CI 1.12-1.51), engaged in low physical activity (OR 2.25, 95% CI 1.05-4.84), and reported liberal sexual attitudes (OR 1.88, 95% CI 1.02-3.47) were more likely to engage in any risky sexual behavior, while frequent alcohol use (OR 8.38, 95% CI 4.60-15.27) and suicide attempts (OR 6.42, 95% CI 2.03-20.29) predicted multiple risky sexual behaviors. In conclusion, this study indicates that Zambian college students' risky sexual behaviors are associated with multiple behavioral health risks. Future research should consider using a multiple-behavior change intervention.

2.
Neurobiol Aging ; 80: 187-195, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31203190

RESUMO

The abnormal proliferation and neurogenesis of neural progenitor cells (NPCs) is usually associated with the pathophysiology of neurodegenerative disorders such as Alzheimer's disease (AD). Mitochondrial stress is one of the most prominent features of AD and is thought to be involved in the impairment of the neurogenesis and proliferation of NPCs. Thus, restoring mitochondrial function by pharmaceutical intervention may alleviate disease-related defects in neurogenesis and is considered a potential therapeutic strategy for AD. In the present study, we found that the oral administration of PL201A, a designed analog of phenylpropanoids, which are a family of natural products with antiaging effects, promoted the neurogenesis and proliferation of NPCs and ameliorated cognitive impairment in a transgenic mouse model of AD. Furthermore, PL201A attenuated amyloid-ß-induced mitochondrial stress and promoted NPC proliferation in vitro. Further mechanistic studies showed that PL201A restored the activation of AMP-regulated protein kinase-retinoblastoma signaling, which was suppressed by amyloid-ß. Our findings suggest that PL201A may represent a promising regenerative therapeutic agent for cognitive decline in neurodegenerative diseases.

3.
Methods Mol Biol ; 1957: 365-384, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30919366

RESUMO

Type II diabetes is one of the most serious worldwide public health problems, and its hallmark is insulin resistance, obesity associated with chronic inflammation, and defective islet ß-cell function. ß-Arrestins play important roles in diabetes pathogenesis through scaffolding insulin-induced AKT activation in the liver, suppressing peroxisome proliferator-activated receptor-γ-mediated adipogenesis and inflammatory responses in adipose tissue and through promoting GLP-1-induced insulin secretion in the islet. The current chapter provides detailed protocols for both in vitro and in vivo studies of the function of ß-arrestins associated with type II diabetes.


Assuntos
Biologia Molecular/métodos , beta-Arrestinas/metabolismo , Adipócitos/metabolismo , Animais , Células da Medula Óssea/citologia , Células Cultivadas , Regulação da Expressão Gênica , Glucose/biossíntese , Hepatócitos/metabolismo , Resistência à Insulina , Secreção de Insulina , Células Secretoras de Insulina/metabolismo , Macrófagos/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Transdução de Sinais , Coloração e Rotulagem
4.
EMBO Rep ; 20(4)2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30872316

RESUMO

Cyclic dinucleotides (CDNs) are important second messenger molecules in prokaryotes and eukaryotes. Within host cells, cytosolic CDNs are detected by STING and alert the host by activating innate immunity characterized by type I interferon (IFN) responses. Extracellular bacteria and dying cells can release CDNs, but sensing of extracellular CDNs (eCDNs) by mammalian cells remains elusive. Here, we report that endocytosis facilitates internalization of eCDNs. The DNA sensor cGAS facilitates sensing of endocytosed CDNs, their perinuclear accumulation, and subsequent STING-dependent release of type I IFN Internalized CDNs bind cGAS directly, leading to its dimerization, and the formation of a cGAS/STING complex, which may activate downstream signaling. Thus, eCDNs comprise microbe- and danger-associated molecular patterns that contribute to host-microbe crosstalk during health and disease.

5.
Sci Rep ; 9(1): 3462, 2019 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-30837577

RESUMO

Glioblastoma (GBM) is the most common and aggressive malignant tumor in adult brain. Even with the current standard therapy including surgical resection followed by postoperative radiotherapy and chemotherapy with temozolomide (Temo), GBM patients still have a poor median survival. Reprogramming of tumor cells into non-malignant cells might be a promising therapeutic strategy for malignant tumors, including GBM. Based on previous studies using small molecules to reprogram astrocytes into neuronal cells, here we further identified a FTT cocktail of three commonly used drugs (Fasudil, Tranilast, and Temo) to reprogram patient-derived GBM cells, either cultured in serum containing or serum-free medium, into neuronal like cells. FTT-treated GBM cells displayed a neuronal like morphology, expressed neuronal genes, exhibited neuronal electrophysiological properties, and showed attenuated malignancy. More importantly, FTT cocktail more significantly suppressed tumor growth and prolonged survival in GBM patient derived xenograft than Temo alone. Our study provided preclinical evidence that the neuronal reprogramming drug cocktail might be a promising strategy to improve the existing treatment for GBM.

6.
J Am Coll Health ; : 1-6, 2019 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-30849021

RESUMO

OBJECTIVE: This study aimed to assess the impact of a health education intervention on health behaviors, self-efficacy, and well-being among college students. PARTICIPANTS: Between March and October 2016, a total of 532 undergraduates participated. METHODS: A theory-based intervention was conducted at Wuhan University, China. Participants were assigned to a control or intervention group (IG). The IG attended a 7-week health education class on knowledge, attitude, and practice of health behaviors. RESULTS: Participants in the IG, compared with those in the control group (CG), reported significantly increased prevalence of high physical activity and regular breakfast, as well as lower screen time, sugar beverage intake, and Internet addiction tendency. Furthermore, intervention students improved in health behavior scores (p = 0.040), compared with the CG, while the changes in subjective well-being and self-efficacy remained similar between the two groups. CONCLUSIONS: Health education may promote health behaviors among Chinese college students.

7.
Neuron ; 101(3): 375-379, 2019 02 06.
Artigo em Inglês | MEDLINE | ID: mdl-30731061

RESUMO

The China Brain Project is in development. Integrating an ethical framework to identify and assess ethical challenges and plan for solutions is a priority. Here Wang et al. discuss ethical questions emerging from brain research in the context of traditional Chinese culture and juxtapose the legacy of Confucianism with contemporary thinking.


Assuntos
Características Culturais , Neurociências/ética , Encéfalo/fisiologia , China , Confucionismo , Humanos , Neurociências/normas
8.
Zhongguo Zhong Yao Za Zhi ; 43(22): 4498-4505, 2018 Nov.
Artigo em Chinês | MEDLINE | ID: mdl-30593245

RESUMO

The potential role of total saponins extracted from Lilium lancifolium bulbs (TSLL) on the proliferation, apoptosis, migration and invasion of human lung cancer A549 cells and its possible mechanism were discussed. Effect of TSLL on proliferation of A549 cells were detected by CCK-8, clone formation assay and EdU staining. Effect of TSLL on apoptosis morphology of A549 cells was observed by fluorescence microscope using Annexin V/PI double staining and Hoechst 33342 staining. Effect of TSLL on cell migration and invasion was detected by Transwell migration test and Transwell invasion test, respectively. Western blot was used to detect TSLL on the expression change of intracellular associated proteins. Results showed that TSLL intervention in A549 cells within 24, 48 or 72 h significantly inhibited cell growth, and its IC50values were about 229, 173 and 71 mg·L⁻¹, respectively. TSLL significantly reduced the clone formation rate of A549 cells and decreased the DNA synthesis rate of A549 cells in a concentration dependent manner. TSLL induced A549 cells apoptosis and reduced the migratory behavior of A549 cells. TSLL decreased invasion of A549 cells to the artificial basement membrane. The expression level of intracellular PCNA and the ratio of Bcl-2/Bax protein were down-regulated and procaspase 3 was activated. In addition, TSLL had no obvious effect on epithelial mesenchymal transition (EMT) related marker proteins E-cadherin and vimentin expression. The above results indicated that TSLL possess inhibitory effects against proliferation, migration and invasion of lung cancer A549 cells and apoptosis-induced effect. The anti-proliferation effect of TSLL is very likely by inhibiting intracellular DNA synthesis through reducing the expression of PCNA in lung cancer cells. And the apoptosis induction of TSLL on lung cancer cells is associated with the regulation of Bcl-2 and Bax proteins expression. Nevertheless, there is no incontestable correlation between anti-invasion and metastasis effects of TSLL and EMT in lung cancer cells.


Assuntos
Neoplasias Pulmonares , Apoptose , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Transição Epitelial-Mesenquimal , Humanos , Invasividade Neoplásica , Metástase Neoplásica , Saponinas
9.
Cell Rep ; 25(6): 1537-1547.e4, 2018 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-30404008

RESUMO

Zika virus (ZIKV) can cause microcephaly in the fetus. However, its effects on body growth and the development of children with postnatal ZIKV infection are largely unknown. To examine this, we intraperitoneally challenged mouse pups with ZIKV. Infection causes an irreversible growth delay and deficits in spatial learning and memory, with growth-relevant hormones significantly reduced during infection. These effects are associated with ZIKV RNA expression in the hypothalamus, blood, and brain but not in the pituitary and thyroid. Infection is also associated with hypothalamic inflammation, and ZIKV antigen is detectable in neuroendocrine cells producing thyrotropin-releasing hormone. Moreover, early administration of growth hormone could significantly improve growth delay. Our results demonstrate that ZIKV can infect the hypothalamus, causing multi-hormone deficiencies and delayed growth and development in a mouse model. Therefore, prospective multidisciplinary follow-up of ZIKV-infected children may be necessary to understand potential effects of this virus on childhood development.

10.
Front Immunol ; 9: 2417, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30405617

RESUMO

Tuberculosis (TB) has tremendous public health relevance. It most frequently affects the lung and is characterized by the development of unique tissue lesions, termed granulomas. These lesions encompass various immune populations, with macrophages being most extensively investigated. Myeloid derived suppressor cells (MDSCs) have been recently identified in TB patients, both in the circulation and at the site of infection, however their interactions with Mycobacterium tuberculosis (Mtb) and their impact on granulomas remain undefined. We generated human monocytic MDSCs and observed that their suppressive capacities are retained upon Mtb infection. We employed an in vitro granuloma model, which mimics human TB lesions to some extent, with the aim of analyzing the roles of MDSCs within granulomas. MDSCs altered the structure of and affected bacterial containment within granuloma-like structures. These effects were partly controlled through highly abundant secreted IL-10. Compared to macrophages, MDSCs activated primarily the NF-κB and MAPK pathways and the latter largely contributed to the release of IL-10 and replication of bacteria within in vitro generated granulomas. Moreover, MDSCs upregulated PD-L1 and suppressed proliferation of lymphocytes, albeit with negligible effects on Mtb replication. Further comprehensive characterization of MDSCs in TB will contribute to a better understanding of disease pathogenesis and facilitate the design of novel immune-based interventions for this deadly infection.

11.
Nature ; 563(7729): 131-136, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30356214

RESUMO

Accurate repair of DNA double-stranded breaks by homologous recombination preserves genome integrity and inhibits tumorigenesis. Cyclic GMP-AMP synthase (cGAS) is a cytosolic DNA sensor that activates innate immunity by initiating the STING-IRF3-type I IFN signalling cascade1,2. Recognition of ruptured micronuclei by cGAS links genome instability to the innate immune response3,4, but the potential involvement of cGAS in DNA repair remains unknown. Here we demonstrate that cGAS inhibits homologous recombination in mouse and human models. DNA damage induces nuclear translocation of cGAS in a manner that is dependent on importin-α, and the phosphorylation of cGAS at tyrosine 215-mediated by B-lymphoid tyrosine kinase-facilitates the cytosolic retention of cGAS. In the nucleus, cGAS is recruited to double-stranded breaks and interacts with PARP1 via poly(ADP-ribose). The cGAS-PARP1 interaction impedes the formation of the PARP1-Timeless complex, and thereby suppresses homologous recombination. We show that knockdown of cGAS suppresses DNA damage and inhibits tumour growth both in vitro and in vivo. We conclude that nuclear cGAS suppresses homologous-recombination-mediated repair and promotes tumour growth, and that cGAS therefore represents a potential target for cancer prevention and therapy.

12.
Am J Transl Res ; 10(8): 2502-2510, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30210688

RESUMO

Portulacae Oleracea L. (POL) is a traditional Chinese medicine and also an edible vegetable used to treat diarrhea in china for thousands years. Though the therapeutic effect has been proved in clinical trials, the concrete effective component and mechanisms remained elusive. Polysaccharide from POL has been extracted previously and the experiment suggested that POLP could diminish the weight loss and improve the health conditions of mice with DSS induced colitis. Hematoxylin & eosin staining revealed that POLP could improve the histopathological structure of the colon tissue. For the notably variation curve of TNF-α in control, colitis and treatment group, NF-κB was enrolled to investigate the molecular mechanisms of the protective effect of POLP. The protein expression level of NF-κBp65 in cytoplasm increased after POLP treatment of the induced colitis. However, the protein level of NF-κBp65 in the nucleus decreased after administration of POLP. The expression levels of IκBα and NF-κB related proteins Bcl-2 and survivin were also detected and the results suggested that POLP could inhibit the degradation of IκBα and decrease the protein levels of Bcl-2 and Survivin in colitis. It was concluded that POLP could improve the health condition of mice with DSS induced colitis and the mechanisms were closely related with NF-κB via inhibiting the degradation of IκBα.

13.
Cell Death Dis ; 9(8): 830, 2018 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-30082779

RESUMO

Neurodegenerative diseases are characterized by a gradual loss of cognitive and physical functions. Medications for these disorders are limited and treat the symptoms only. There are no disease-modifying therapies available, which have been shown to slow or stop the continuing loss of neurons. Transdifferentiation, whereby somatic cells are reprogrammed into another lineage without going through an intermediate proliferative pluripotent stem cell stage, provides an alternative strategy for regenerative medicine and disease modeling. In particular, the transdifferentiation of somatic cells into specific subset of patient-specific neuronal cells offers alternative autologous cell therapeutic strategies for neurodegenerative disorders and presents a rich source of using diverse somatic cell types for relevant applications in translational, personalized medicine, as well as human mechanistic study, new drug-target identification, and novel drug screening systems. Here, we provide a comprehensive overview of the recent development of transdifferentiation research, with particular attention to chemical-induced transdifferentiation and perspectives for modeling and treatment of neurodegenerative diseases.

14.
Front Aging Neurosci ; 10: 169, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29922152

RESUMO

Alzheimer's disease (AD) is a multi-factorial neurodegenerative disorder with abnormal accumulation of amyloid-ß (Aß) plaques, neuroinflammation and impaired neurogenesis. Mounting evidences suggest that single-target drugs have limited effects on clinical treatment and alternative or multiple targets are required. In recent decades, natural compounds and their derivatives have gained increasing attention in AD drug discovery due to their inherently enormous chemical and structural diversity. In this study, we demonstrated that naringin dihydrochalcone (NDC), a widely used dietary sweetener with strong antioxidant activity, improved the cognitive function of transgenic AD mice. Pathologically, NDC attenuated Aß deposition in AD mouse brain. Furthermore, NDC reduced periplaque activated microglia and astrocytes, indicating the inhibition of neuroinflammation. It also enhanced neurogenesis as investigated by BrdU/NeuN double labeling. Additionally, the inhibition of Aß level and neuroinflammation by NDC treatment was also observed in an AD cell model or a microglia cell line. Taken together, our study indicated that NDC might be a potential therapeutic agent for the treatment of AD against multiple targets that include Aß pathology, neuroinflammation and neurogenesis.

15.
Bioresour Technol ; 264: 261-267, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29852415

RESUMO

In this work, p-hydroxybenzenesulfonic acid-formaldehyde resin acid catalyst (MSPFR), was synthesized by a hydrothermal method, and employed for the furfural production from raw corn stover. Scanning electron microscopy (SEM), transmission electron microscopy (TEM), N2 adsorption-desorption, elemental analysis (EA), thermogravimetric analysis (TGA), and Fourier transform infrared spectroscopy (FT-IR) were used to characterize the MSPFR. The effects of reaction time, temperature, solvents and corn stover loading were investigated. The MSPFR presented high catalytic activity for the formation of furfural from corn stover. When the MSPFR/corn stover mass loading ratio was 0.5, a higher furfural yield of 43.4% could be achieved at 190 °C in 100 min with 30.7% 5-hydroxymethylfurfural (HMF) yield. Additionally, quite importantly, the recyclability of the MSPFR for xylose dehydration is good, and for the conversion of corn stover was reasonable.


Assuntos
Furaldeído/química , Zea mays , Ácidos , Formaldeído , Espectroscopia de Infravermelho com Transformada de Fourier
16.
Zhongguo Zhong Yao Za Zhi ; 43(7): 1416-1426, 2018 Apr.
Artigo em Chinês | MEDLINE | ID: mdl-29728031

RESUMO

Genus Lilium plants contain a variety of steroidal saponins, so far at least 82 steroidal saponins have been found in the bulbs of Lilium species, including 13 spirostanol saponins (1-13), 39 isospirostanol saponins (14-52), 7 pseudospirostanol saponins (53-59), and 23 furostanol saponins (60-82). Studies have showed that these steroidal saponins exhibit a wide range of pharmacological activities, including antitumor, antibacterial, antiinflammatory, antioxidant, antidepressant, hepatoprotective, hypoglycemic, sedative-hypnotic effect, and inhibition of cAMP phosphodiesterase and Na⁺-K⁺ ATP, et al. This paper has classified and summarized the 82 steroidal saponins isolated and identified from the bulbs of Lilium species and their correlative biological activities. Also, their structural characteristics and structure-activities relationship have been discussed, which could provide references for further research and application development of Lilium plants.

17.
Phytomedicine ; 41: 54-61, 2018 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-29519319

RESUMO

BACKGROUND: Gnaphalium affine D. Don is a folk medicine of China believed to be efficacious in the treatment of many ailments, including hyperuricemia and gout. PURPOSE: Based on a previous study, we isolated two flavones, luteolin and luteolin-4'-O-glucoside, from G. affine. Our aim was to assess the potential beneficial effects of treatment and mechanisms of these two flavones on hyperuricemia and acute gouty arthritis. METHODS: The model of potassium oxonate (PO)-induced hyperuricemia and monosodium urate (MSU) crystal-induced inflammation in mice has been established. We evaluated serum uric acid (Sur), xanthine oxidase (XO) activity, protein expression of urate transporter 1 (mURAT1) and glucose transporter 9 (mGLUT9) in renal and kidney protection in a hyperuricemia model. In addition, paw swelling and levels of interleukin-1ß (IL-1ß) and tumor necrosis factor-α (TNF-α) in serum were assessed in MSU crystal-induced mice. RESULTS: Luteolin and luteolin-4'-O-glucoside showed a potent clinical effect in treating hyperuricemia and gout. We observed that the two flavones possess potent effect in hyperuricemia mice by decreasing the level of mURAT1 and inhibiting XO activity, which contribute to enhancing uric acid (UA) excretion and improving hyperuricemia-induced renal dysfunction. In addition, luteolin and luteolin-4'-O-glucoside also alleviated paw swelling and inflammation induced by MSU crystals. Further investigation implied that luteolin and luteolin-4'-O-glucoside improved the symptoms of inflammation by decreasing the levels of IL-1ß and TNF-α. CONCLUSION: The present study suggests that luteolin and luteolin-4'-O-glucoside could be developed as therapeutics for treating hyperuricemia and gouty arthritis.


Assuntos
Artrite Gotosa/tratamento farmacológico , Glucosídeos/farmacologia , Gnaphalium/química , Hiperuricemia/tratamento farmacológico , Luteolina/farmacologia , Animais , Artrite Gotosa/induzido quimicamente , Modelos Animais de Doenças , Medicamentos de Ervas Chinesas/química , Edema/tratamento farmacológico , Proteínas Facilitadoras de Transporte de Glucose/metabolismo , Hiperuricemia/metabolismo , Interleucina-1beta/metabolismo , Rim/metabolismo , Masculino , Camundongos Endogâmicos ICR , Transportadores de Ânions Orgânicos/metabolismo , Ácido Úrico/sangue , Ácido Úrico/toxicidade , Xantina Oxidase/metabolismo
18.
FASEB J ; 32(8): 4096-4106, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29485902

RESUMO

ß-Arrestins (ß-arrestin-1 and -2) are multifunctional proteins that play important roles in the regulation of inflammation and cell survival that need to be tightly controlled; however, the mechanism that underlies their gene expression is largely unclear. Here, we demonstrate that ß-arrestin-1 is a transcriptional target of NF-κB. mRNA and protein levels of ß-arrestin-1 were up-regulated by NF-κB inducers. Inhibition of NF-κB prevented the up-regulation of ß-arrestin-1 mRNA, whereas activation of NF-κB led to increased ß-arrestin-1 expression. ß-Arrestin-1 promoter activity was consistently enhanced upon NF-κB activation as a result of the presence of a highly conserved κB site. ß-Arrestin-1, in turn, suppressed the transcriptional activity of NF-κB by interfering with the interaction between p65 and p50. ß-Arrestin-1-deficient mice displayed reduced TNF-α-induced cell death and increased expression of antiapoptotic genes. Reintroduction of ß-arrestin-1, but not its mutant, which is unable to interfere with the p65-p50 interaction, into ß-arrestin-deficient mouse embryonic fibroblasts partially restored sensitivity to TNF-α-induced cell death. These findings reveal NF-κB and ß-arrestin-1 to be key components of a negative feedback circuit that is necessary to regulate cell death.-Li, J., Guo, A., Wang, Q., Li, Y., Zhao, J., Lu, J., Pei, G. NF-κB directly regulates ß-arrestin-1 expression and forms a negative feedback circuit in TNF-α-induced cell death.

19.
J Mol Cell Biol ; 10(5): 411-422, 2018 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-29325091

RESUMO

α-secretase and ß-secretase are known to compete for amyloid precursor protein (APP) processing and thus play a vital role in Alzheimer's disease pathogenesis. A disintegrin and metalloproteinase 10 (ADAM10) and ß-site APP cleaving enzyme 1 (BACE1) mediate the major activities of α-secretase and ß-secretase in brain and share various common substrates. However, whether they function separately or together is poorly understood. Here, we show that ADAM10 and BACE1 co-localize in the neurites of mouse primary neurons. Co-immunoprecipitation and fluorescence resonance energy transfer analysis revealed that ADAM10 and BACE1 interact with each other under both endogenous and exogenous conditions. In addition, we found that ADAM10 enhances the proteolysis of neural cell adhesion molecule close homolog of L1 (CHL1) by BACE1. Further studies found that ADAM10-BACE1 interaction interfering peptide LT52 attenuates the regulation of ADAM10 on BACE1-mediated cleavage of CHL1. Our data indicate that ADAM10-BACE1 interaction regulates the proteolysis of some specific substrates and may play a potential role in brain function.

20.
Autophagy ; 13(12): 2041-2055, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29251248

RESUMO

The E3 ubiquitin ligase NEDD4 has been intensively studied in processes involved in viral infections, such as virus budding. However, little is known about its functions in bacterial infections. Our investigations into the role of NEDD4 in intracellular bacterial infections demonstrate that Mycobacterium tuberculosis and Listeria monocytogenes, but not Mycobacterium bovis BCG, replicate more efficiently in NEDD4 knockdown macrophages. In parallel, NEDD4 knockdown or knockout impaired basal macroautophagy/autophagy, as well as infection-induced autophagy. Conversely, NEDD4 expression promoted autophagy in an E3 catalytic activity-dependent manner, thereby restricting intracellular Listeria replication. Mechanistic studies uncovered that endogenous NEDD4 interacted with BECN1/Beclin 1 and this interaction increased during Listeria infection. Deficiency of NEDD4 resulted in elevated K48-linkage ubiquitination of endogenous BECN1. Further, NEDD4 mediated K6- and K27- linkage ubiquitination of BECN1, leading to elevated stability of BECN1 and increased autophagy. Thus, NEDD4 participates in killing of intracellular bacterial pathogens via autophagy by sustaining the stability of BECN1.

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